This group works on gene regulation in the immune system. During this period we have worked on the function of ICSBP, an immune system specific transcription factor belonging to the interferon regulatory factor (IRF) family. Interferong (IFNg), once called macrophage activating factor, is critical for innate immunity elicited by macrophages. ICSBP is a factor induced by IFNg in macrophages. Previous work with ICSBP-/- mice showed that this factor required for expression of IL-12, a macrophage cytokine critical for IFNg production. Here, we found that ICSBP plays an important role in IFNg mediated signaling in macrophages. Our work began with the observation that transcription mediated through the GAS element is impaired in ICSBP-/- macrophages. GAS is a small palindromic regulatory element through which STAT1 stimulates transcription of IFNg responsive genes. We demonstrated that ectopic expression of ICSBP stimulates GAS dependent transcription to a level comparable to that by IFNg itself. This activation was seen even without IFNg treatment. Furthermore, ICSBP when transfected into STAT1 negative fibroblasts, activated GAS mediated promoter activity, indicating that ICSBP acts through GAS. These results were substantiated by the finding that ICSBP is recruited to the GAS element through protein-protein interactions. Taken together our results indicate that ICSBP activates IFNg responsive genes via a novel pathway, which presumably contribute to the biological activities of IFNg specific for macrophages. As a separate effort, we investigated the mechanism by which thyroid hormone (T3) represses thyrotropin gene transcription. This repression is dependent on the thyroid hormone receptor (TR), a member of the nuclear receptor superfamily. Having identified the negative regulatory element (NRE) involved in repression, we investigated recruitment of nuclear factors to the NRE. We found that histone deacetylases (HDACs) are recruited to the element in a T3 dependent manner, coinciding with recruitment of TR. TR is known to recruit histone acetylases (HATs) to a positive regulatory element through which T3 activates transcription. Thus, nuclear receptor-mediated transcriptional activation and repression is regulated through differential recruitment of histone acetylases and deacetylases.